Cognitive flexibility is an essential prerequisite for goal-directed behavior, and daily observations already show that it deteriorates when one is engaged in a task for a (too) long time. Yet, the neural mechanisms underlying such fatigability effect in cognitive flexibility are poorly understood. We examined how theta, alpha, and beta frequency event-related synchronization and desynchronization processes during cued memory-based task switching are modulated by time-on-task effects. We put special emphasis on the examination of functional neuroanatomical regions being associated with these modulations, using EEG beamforming. We show clear declines in task switching performance (increased switch costs) with time on task. For processes occurring before rule switching or repetition processes, we show that anticipatory attentional sampling and selection mechanisms associated with fronto-parietal structures are modulated by time-on-task effects but sensory areas (occipital cortex) also show fatigability-dependent modulations. After target stimulus presentation, the allocation of processing resources for response selection as reflected by theta-related activity in parietal cortices is compromised with time on task and similarly a concomitant increase in alpha and beta band-related attentional processing or gating mechanisms in frontal and occipital regions. Yet, considering the behavioral data showing an apparent decline in performance, this probably compensatory increase is still insufficient to allow reasonable performance. The same is likely the case for processes occurring before rule switching or repetition processes. Comparative analyses show that modulations of alpha band activity are as strongly modulated by fatigability as theta band activity. Implications of these findings for theoretical concepts on fatigability are discussed. NEW & NOTEWORTHY We examine the neurophysiological and functional neuroanatomical basis of fatigability in cognitive flexibility. We show that alpha and theta modulations in fronto-parietal and primary sensory areas are central for the understanding of fatigability effects in cognitive flexibility.